Regulation of B cell proliferation and differentiation by retinoic acid.
ABSTRACT Vitamin A protects against development of infectious diseases, and B cells are important players in this process. Keys to the protective role of retinoic acid (RA) against infections appear to be its ability to enhance antibody responses against T-cell dependent and independent type 2 antigens, as well as to locally stimulate IgA production in mucosal tissues. The elucidation of molecular mechanisms involved in RA-mediated regulation of proliferation and differentiation of B cells not only helps us to understand how RA differentially regulates subsets of B cells, but might also lead to more targeted treatment of selected immune disorders and B cell malignancies.
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ABSTRACT: Mice fed a semipurified, vitamin A-deficient diet (A- mice) and control animals fed the same diet with added retinyl acetate (A+ mice) were used to investigate the effect of vitamin A deficiency on primary immunoglobulin responses to protein antigens. At age 6 weeks, A- mice had serum retinol concentrations that were 46% of A+ controls. When immunized with a single antigen dose, these mice produced an antigen-specific IgM response equivalent to controls, but their IgG1 and IgG3 responses were sharply diminished (less than 30% of A+ controls). At age 8 weeks, A- mice had 20% of A+ serum retinol concentrations and less than 17% of A+ liver retinyl palmitate levels. Responding to a single antigen dose, A- mice produced approximately equal to 70% as much IgM as A+ controls. Their IgG1 response was less than 30% and their IgG3 response less than 3% of A+ controls. The IgG1 response kinetics were identical in A- and A+ mice. Diminished serum antibody responses in A- mice were attributable to fewer immunoglobulin-secreting plasma cells rather than to a decline in IgM or IgG secretion rate per cell. Total serum IgG3 levels, irrespective of antigen specificity, were slightly elevated in A- mice compared to A+ controls. The inefficient clonal expansion of responding B lymphocytes and contrasting impairment of IgM and IgG responses observed in vitamin A-deficient mice are discussed with respect to a possible helper/inducer-T-lymphocyte defect.Proceedings of the National Academy of Sciences 09/1987; 84(16):5878-82. · 9.74 Impact Factor
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ABSTRACT: For a preferential homing of T cells to the gut, expression of the integrin alpha4beta7 and the chemokine receptor CCR9 is essential and is induced by antigenic stimulation with dendritic cells from the gut-associated lymphoid organs. Here, we show that the vitamin A (retinol) metabolite, retinoic acid, enhances the expression of alpha4beta7 and CCR9 on T cells upon activation and imprints them with the gut tropism. Dendritic cells from the gut-associated lymphoid organs produced retinoic acid from retinol. The enhanced alpha4beta7 expression on T cells by antigenic stimulation with these dendritic cells was suppressed by the retinal dehydrogenase inhibitor citral and the retinoic acid receptor antagonist LE135. Accordingly, vitamin A deficiency caused a reduction in alpha4beta7(+) memory/activated T cells in lymphoid organs and a depletion of T cells from the intestinal lamina propria. These findings revealed a novel role for retinoic acid in the imprinting of gut-homing specificity on T cells.Immunity 11/2004; 21(4):527-38. · 19.80 Impact Factor
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ABSTRACT: We showed the dose-dependent growth inhibition by alltrans retinoic acid (ATRA) of myeloma cells freshly isolated from patients. ATRA downregulated the cell surface expression of interleukin-6 receptor (IL-6R) and/or glycoprotein (gp) 130. The growth-inhibitory activity of ATRA was well correlated with that of anti-gp 130 antibody in every sample. Furthermore, ATRA inhibited the production of IL-6 from both myeloma cells and marrow stromal cells, and recombinant IL-6 (rIL-6) could partially recover the myeloma cell growth that had been inhibited by ATRA. These data suggest that ATRA may inhibit the proliferation of myeloma cells both by the downregulation of IL-6R and gp130 expression on myeloma cells and by the inhibition of IL-6 production from myeloma and stromal cells. Prednisolone (PSL) and interferon-gamma (IFN-gamma) also inhibited the myeloma growth, while their effects were different from those of ATRA on IL-6 R and gp130 expression, IL-6 production, and morphological change. The inhibitory effect of ATRA on myeloma cell proliferation was observed in 10 of 14 samples obtained from eight patients, which suggests that ATRA may be a potent new therapeutic agent for some myeloma patients.Blood 12/1994; 84(9):3040-6. · 9.06 Impact Factor